Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration

Giroux, Véronique; Lento, Ashley; Islam, Mirazul; Pitarresi, Jason R.; Kharbanda, Akriti; Hamilton, Kathryn E.; Whelan, Kelly A.; Long, Apple; Rhoades, Ben; Tang, Qiaosi; Nakagawa, Hiroshi; Lengner, Christopher J.; Bass, Adam J.; Wileyto, E. Paul; Klein‐Szanto, Andres J.; Wang, Yichen; Rustgi, Anil K.

doi:10.1172/jci88941

Cited by 96 publications

(106 citation statements)

References 41 publications

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“…Intrigued by the possibility that modulating the immediate environment of the primordium might lead to a modulation of pLL patterns, we decided to disrupt epithelial integrity by targeting keratin 15 (krt15) using Crispr/Cas9 (see M&M). Both F0 crispants and stable mutants (Supplementary Figure 1) showed epithelial extrusion (Figure 4A,B white arrows), perturbations in the structural integrity and cellular packing in the supra-basal epithelial layer (Figure 4 C-D, N=>100 cells segmented in wt and krt15 mutants, N= 5 control & 15 krt15 mutants larvae), lesions in the basal epithelium (Figure 4 F-G’ N>10 embryos) and epithelial cell death (Figure 4 G-G’ magenta arrows N=5 embryos) as revealed by nuclear rounding and cell membrane shrinkage, all in line with known Krt15 functions in epithelial cells (Bose et al, 2013; Chamcheu et al, 2011; Giroux et al, 2017; Giroux et al, 2018; Haines and Lane, 2012; Liu et al, 2003; Peters et al, 2001). In addition, krt15 crispants and mutants showed a perturbed lateral line pattern, with primary organs locating to the midline (Figure 4 E-G’).…”

Section: Resultssupporting

confidence: 66%

Tissue interactions govern pattern formation in the posterior lateral line of medaka

Seleit

Gross

Onistschenko

et al. 2020

Preprint

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1 Vertebrate organs are arranged in a stereotypic, species-specific position along the animal body 2 plan. Substantial morphological variation exists between related species, especially so in the vastly 3 diversified teleost clade. It is still unclear how tissues, organs and systems can accommodate such 4 diverse scaffolds. Here, we use the sequential formation of neuromasts in the posterior lateral line 5 (pLL) system of medaka fish to address tissue-interactions defining a pattern. We show that the 6 pLL pattern is established independently of its neuronal wiring, and demonstrate that the neuromast 7 precursors that constitute the pLL behave as autonomous units during pattern construction. We 8 uncover the necessity of epithelial integrity for correct pLL patterning by disrupting keratin 15 (krt15) 9 and creating epithelial lesions that lead to novel neuromast positioning. By using krt15/wt chimeras, 10 we determined that the new pLL pattern depends exclusively on the mutant epithelium, which 11 instructs wt neuromast to locate ectopically. Inducing epithelial lesions by 2-photon laser ablation 12 during pLL morphogenesis phenocopies krt15 genetic mutants and reveals that epithelial integrity 13 defines the final position of the embryonic pLL neuromasts. Our results show that a fine-balance 14 between primordium intrinsic properties and instructive interactions with the surrounding tissues is 15 necessary to achieve proper organ morphogenesis and patterning. We speculate that this logic 16 likely facilitates the accommodation of sensory modules to changing and diverse body plans.

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Section: Resultssupporting

confidence: 66%

Tissue interactions govern pattern formation in the posterior lateral line of medaka

Seleit

Gross

Onistschenko

et al. 2020

Preprint

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“…As a further validation, we tested our parameterized model against a third, more limited dataset from Krt15-cre PR1 R26 mT/mG mice in which a red-to-green fluorescent reporter was used with inducible Cre expressed from a Krt15 promoter (Suppl. Methods) 29 . Although the SP paradigm was criticized by these authors, it yielded an adequate fit with their own data over the experimental time course ( Fig.…”

Section: Methods)mentioning

confidence: 99%

“…Data from lineage tracing in scale and interscale tail epidermis 20 was accessed through the online publication material, while authors were unable to provide original data from 4 . Data on Krt15-cre PR1 R26 mT/mG mouse esophagus 29 were retrieved by digitalizing Fig. 2E and Fig.…”

Section: Wholemount Preparation and Immunostainingmentioning

confidence: 99%

The single-progenitor model as the unifying paradigm of squamous epithelial maintenance

Piedrafita

Kostiou

Wabik

et al. 2019

Preprint

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Adult tissues such as the epidermis of the skin and the epithelium lining the esophagus are continuously turned over throughout life. Cells are shed from the tissue surface and replaced by cell division. Yet, the cellular mechanisms that underpin these tissues homeostasis remain poorly established, having important implications for wound healing and carcinogenesis. Lineage tracing, in which of a cohort of proliferating cells and their descendants are genetically labelled in transgenic mice, has been used to study the fate behavior of the proliferating cells that maintain these tissues. However, based on this technique, distinct mutually irreconcilable models, differing in the implored number and hierarchy of proliferating cell types, have been proposed to explain homeostasis. To elucidate which of these conflicting scenarios should prevail, here we performed cell proliferation assays across multiple body sites in transgenic H2BGFP mouse epidermis and esophagus. Cell-cycle properties were then extracted from the H2BGFP dilution kinetics and adopted in a common analytic approach for a refined analysis of a new lineage-tracing experiment and eight published clonal data sets from esophagus and different skin territories. Our results show H2BGFP dilution profiles remained unimodal over time, indicating the absence of slow-cycling stem cells across all tissues analyzed. We find that despite using diverse genetic labelling approaches, all lineage-tracing data sets are consistent with tissues maintenance by a single population of proliferating cells. The outcome of a given division is unpredictable but, on average the likelihood of producing proliferating and differentiating cells is balanced, ensuring tissue homeostasis. The fate outcomes of sister cells are anticorrelated. We conclude a single cell population maintains squamous epithelial homeostasis.

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“…The true identity of the original cells remains to be established; alternatively, gene reprogramming might be occurring in progenitor cells, or possibly in differentiated cells, as rare events that trigger metaplasia. Notably, long-lived stem cells have been identified in both human and mouse oesophagus and stomach 86–89 , with compelling evidence obtained in the oesophagus from lineage tracing in a genetic mouse model in which keratin 15 (KRT15) + oesophageal basal cells are long-lived and contribute to tissue regeneration after radiation injury.…”

Section: Expansion Of Metaplastic Clonesmentioning

confidence: 99%

Metaplasia: tissue injury adaptation and a precursor to the dysplasia–cancer sequence

2017

Self Cite

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Metaplasia is the replacement of one differentiated somatic cell type with another differentiated somatic cell type in the same tissue. Typically, metaplasia is triggered by environmental stimuli, which may act in concert with the deleterious effects of microorganisms and inflammation. The cell of origin for intestinal metaplasia in the oesophagus and stomach and for pancreatic acinar–ductal metaplasia has been posited through genetic mouse models and lineage tracing but has not been identified in other types of metaplasia, such as squamous metaplasia. A hallmark of metaplasia is a change in cellular identity, and this process can be regulated by transcription factors that initiate and/or maintain cellular identity, perhaps in concert with epigenetic reprogramming. Universally, metaplasia is a precursor to low-grade dysplasia, which can culminate in high-grade dysplasia and carcinoma. Improved clinical screening for and surveillance of metaplasia might lead to better prevention or early detection of dysplasia and cancer.

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Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration

Cited by 96 publications

References 41 publications

Tissue interactions govern pattern formation in the posterior lateral line of medaka

Tissue interactions govern pattern formation in the posterior lateral line of medaka

The single-progenitor model as the unifying paradigm of squamous epithelial maintenance

Metaplasia: tissue injury adaptation and a precursor to the dysplasia–cancer sequence

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